Pain sensation in neuropathic pain is complex consisting of weakness, sensory deficits and numbness, reflex changes, abnormal sensations that occur either spontaneously or in reaction to external stimuli, hyperalgesia and allodynia. Perturbations in dorsal root ganglion (DRG) neuron excitability are key in precipitating neuropathic pain, especially during diabetes, the most common cause of neuropathic pain. During diabetes, the p38 mitogen-activated protein kinase (p38MAPK) signaling system is activated and when this pathway is inhibited, diabetes-induced neuropathic pain is attenuated. However, the major ion conductances involved in the neuropathic process of DRG neurons are unclear. DRG neurons possess high levels of a novel, understudied family of potassium channels called sodium-activated potassium channels (KNa). Our previous work has shown that KNa is a considerable component of the outward potassium current and is responsible for firing accommodation in DRG neurons. When we experimentally reduce the expression of these channels in DRG neurons, it produces hyperexcitability that resembles neuropathic neurons. There are two genes encoding these channels, Slack and Slick. In heterologous expression systems, the Slick and Slack subunits can co-assemble to form heteromeric channels systems with very slow activation kinetics ideal for controlling firing accommodation. Moreover, homomeric Slick channels appear to be subject to Nedd4l-dependent ubiquitination, suggesting that Slack/Slick heteromeric channels are the preferred configuration of native KNa channels. Slack and Slick also have p38MAPK consensus phosphorylation sites proximal to the sodium binding/gating region of the channels. A decrease in KNa channel activity likely ensues after diabetes-activated p38MAPK signaling. Since diabetes also affects transcriptional activities, we expect to find long-term changes in KNa channel expression in neurons. Using electrophysiological, biochemical, molecular, pain behavioral assays and a previously uncharacterized Slick knockout mouse, we will test the hypotheses: heteromeric KNa channels constrain sensory neuron hyperexcitability and neuropathic pain is associated with decreased KNa channel activity in DRG neurons. The specific aims are (1) To study the regulation of DRG KNa channels by p38MAPK (2) To investigate the subunit properties of KNa channels in DRG neurons (3) To study neuronal KNa channel activity during diabetes and compare pain behavior to Slick knockout mice. This research project will assess the involvement of KNa channels in the diabetic neuropathy. PUBLIC HEALTH RELEVANCE: Elucidating the mechanisms underlying persistent pain in peripheral neuropathy is of vital importance for future treatment strategies. This proposal is designed to determine how sodium-activated potassium channels regulate sensory neuron excitability and if they are down regulated during neuropathic pain. The conclusions of these studies may identify these channels as analgesic targets for neuropathic pain.